The present invention is directed to retinyl ethers and derivatives and their use in inhibiting breast carcinogenesis or breast cancer cell growth.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the following text and respectively grouped in the appended List of References. All patents and published patent applications are incorporated herein by reference.
It is well established that retinoids are prime candidates for the prevention of some forms of cancer. Numerous studies in experimental models of cancer in animals have demonstrated that certain retinoids suppress or delay the development of carcinogen-induced malignances (Sporn, 1977; Sporn, 1980; Hill and Gribbs, 1982; Sporn and Roberts, 1984, Hill and Grubbs, 1992; Moon et al., 1994). Initially, some of the natural retinoids, e.g., retinol (or retinyl esters), retinoic acid (or retinoates), retinal, 13-cis-retinoic acid, were found to exert cancer chemopreventative effects in vivo (Sporn, 1977; Hill and Grubbs, 1982; Sporn and Roberts, 1984; Moon and Itri, 1984; Sporn et al., 1976). However, the usefulness of natural retinoids for cancer chemoprevention is limited because of their toxicity in pharmacological doses, storage of retinyl esters in the liver and the resulting hepatotoxicity, inadequate target-organ specificity and insufficient accumulation in target organs (Sporn, 1977; Sporn, 1980; Sporn et al., 1976). This has led to the study of retinoid derivatives for use as chemopreventative agents.
There are many reports, which have been summarized previously (Lotan et al., 1980; Shealy, 1989) that retinyl methyl ether (RME) is active in various bioassays in vitro. In addition, RME has been shown to suppress 7,12-DMBA-induced (Grubbs el al, 1977) and MNU-induced (Thompson et al., 1978) mammary cancer in rats. However, as pointed out previously (Shealy, 1989; Shealy et al., 1997) reports of the demethylation of RME by microsomal oxidases to retinol (Thompson and Pitt, 1963; Narindrasorasak et al., 1971; Narindrasorasak and Laksmanan, 1972) apparently discouraged further investigations of RME and other retinyl ethers. Nevertheless, the rationale for reviving investigations of retinyl ethers was outlined (Shealy, 1989) and became the basis for the synthesis of new retinyl ethers, especially, for evaluation against carcinogen-induced mammary cancer. It was postulated that some new retinyl ethers -unlike RME -might not be converted to retinol, but might accumulate in mammary tissue.
Two of the new retinyl ethers, retinyl propynyl ether (RPE) and retinyl 3-methyl-2-butenyl ether (RMBE), inhibited the development of MNU-induced mammary cancer (Shealy et al., 1997). During these studies, it was shown that RPE accumulated in rat mammary tissue and that RPE and RMBE did not cause (because of the low- or non-conversion of these derivatives to retinol) accumulation of large amounts of retinyl palmitate in the liver, a toxic effect produced by efficacious amounts of retinyl acetate or RME. RMBE was only modestly active in the 90-day anti-carcinogenesis study. RPE appeared to be more effective than retinyl acetate (the positive control retinoid), but it slowly undergoes an intramolecular Diels-Alder reaction in the solid state and in solution (Shealy et al., 1996, 1997), and also causes some increase in retinyl palmitate in the liver.
Thus, it is desired to identify additional retinyl ether derivatives which have chemopreventative activity and can be used to inhibit carcinogenesis, especially breast carcinogenesis, or to inhibit breast cancer cell growth, and which do not have disadvantages of prior retinyl ethers.